Abnormal cells in the body are known to selectively absorb certain dyes that have been perfused into a treatment site to a much greater extent than absorbed by surrounding tissue. For example, tumors of the pancreas and colon may absorb two to three times the volume of certain dyes, compared to normal cells. Once pre-sensitized by dye tagging in this manner, the cancerous or abnormal cells can be destroyed by irradiation with light of an appropriate wavelength or waveband corresponding to an absorbing wavelength or waveband of the dye, with minimal damage to surrounding normal tissue. The procedure that uses light to destroy undesirable tissue, known by the acronym PDT, has been clinically used to treat metastatic breast cancer, bladder cancer, lung carcinomas, esophageal cancer, basal cell carcinoma, malignant melanoma, ocular tumors, head and neck cancers, and other types of malignant tissue growths. Because PDT selectively destroys abnormal cells that have absorbed more of a photoreactive dye than normal cells, it can successfully be used to kill malignant tissue with less effect on surrounding benign tissue than alternative treatment procedures.
In typical applications of PDT, the light used in PDT is administered to an internal treatment site through an optical fiber from an external source such as a laser or is applied to a site exposed during a surgical procedure. However, alternative techniques exist to provide light therapy. For example, several different embodiments of implantable light emitting probes for administering photodynamic therapy (PDT) to an internal site within a patient's body are disclosed in commonly assigned U.S. Pat. No. 5,445,608. Further, a number of embodiments of flexible light emitting probes are disclosed in commonly assigned pending U.S. patent application, Ser. No. 08/613,390, and a continuation-in-part patent application thereof, Ser. No. 08/633,171, both entitled, "Flexible Microcircuits for Internal Light Therapy." The above-referenced U.S. Pat. No. 5,445,608 teaches that an implantable probe containing a plurality of light sources can be transcutaneously introduced to a desired treatment site through a surgical incision and then left in place for an extended period of time so that the light emitted by light emitting diodes (LEDs) or other types of light sources mounted in the probe can administer PDT to destroy abnormal tissue or other types of pathogenic organisms that have absorbed an appropriate photoreactive agent. Similarly, the flexible microcircuits disclosed in the above-noted pending patent applications are generally intended to be introduced into the body through a natural opening or through a small incision and positioned at the treatment site using conventional endoscopic techniques. The flexibility of these microcircuits facilitates their insertion into the body and disposition at the treatment site.
Several studies have investigated the relationship between the immunological system and PDT in the treatment of cancerous tumors. For example, in an article entitled "Evidence for an Important Role of Neutrophils in the Efficacy of Photodynamic Therapy in Vivo," Wil J. A. de Vree et al., Cancer Research, Vol. 56, pp. 2908-2911, Jul. 1, 1996, it is noted that administration of a granulocyte-colony stimulating factor (G-CSF) two days before PDT was started led to a fourfold increase in the number of circulating neutrophils and a retarded tumor growth in rats, compared to those injected with saline solution before receiving the PDT. The article postulates the following explanation for this effect.
" . . . (N)eutrophils might adhere via .beta..sub.2 -integrins to stretches in the vascular wall where endothelium as a result of PDT has contracted, and where the subendothelial matrix is exposed, as reported previously. Neutrophils, most likely attracted by chemotactic factors, could infiltrate the tumor area, releasing proteolytic enzymes that degrade attenuated tumor cells, which otherwise may continue to proliferate."
It is noted in the article that PDT had no effect on tumor growth in the absence of neutrophils--a condition achieved in the research by administering antigranulocyte antiserum.
In another article entitled "Potentiation of Photodynamic Therapy-elicited Antitumor Response by Localized Treatment with Granulocyte-Macrophage Colony-stimulating Factor," Gorazd Krosl et al., Cancer Research, Vol. 56, pp. 3281-3286, Jul. 15, 1996, the authors reported on experiments in which granulocyte-macrophage colony stimulating factor (GM-CSF) was administered three times in 48-hour intervals, beginning two days before PDT was administered and noted that the GM-CSF substantially improved the beneficial results of PDT in treating squamous cell carcinoma (SCCVII) cells. It was found that GM-CSF alone failed to provide any obvious benefit in treating a tumor. The research indicates that the GM-CSF treatment "increases the cytotoxic activity of tumor-associated macrophages against (SCCVII) tumor cells" and that "tumor-localized immune stimulation by GM-CSF amplifies a PDT-induced antitumor immune reaction, which has a potentiating effect on tumor control." It was noted that tumors treated with PDT are believed to be eradicated due to a combination of several different effects, including: (1) photooxidative damage to vital cellular structure; (2) inactivation of tumor cells by ischemia secondary to the damage of the tumor vasculature and by integrated tumoricidal activity of nonspecific and specific immune effector cells; and, (3) a host response dominated by a strong tumor-localized acute inflammatory reaction associated with the functional activation of tumor resident and newly arrived leukocytes. It is suggested by the reference that neutrophils, mast cells, monocytes, and macrophages participate in the antitumor activity in an early phase after PDT treatment, and that the release and phagocytosis of tumor cell debris following the destruction of tumor cells creates a condition for the processing and presentation of tumor antigens by macrophages and dendritic cells or other antigen-presenting cells, resulting in development of tumor-specific immunity.
In another article, "Enhanced Macrophage Cytotoxicity against Tumor Cells Treated with Photodynamic Therapy," Photochemistry and Photobiology, Vol. 60, No. 5, pp. 497-502, 1994, Mladen Korbelik and Gorazd Krosl, the authors report that they were led to investigate the cytotoxic activity of macrophages against PDT-treated target tumor cells based on related work performed by other researchers. Specifically, the article refers to earlier research indicating that due to the extensive damage of the membrane structure of tumor cells caused by PDT, affected tumor cells release alkylglycerols, lysophospholipids, and alkyllysophospholipids, which have been identified as potent macrophage stimulating agents. Release of these agents are thus believed to lead to an enhanced macrophagic destruction of tumor cells. The article reported that an enhanced macrophage-mediated killing of tumor cells treated by PDT was observed for two different types of macrophages, including peritoneal macrophages and macrophages differentiated from cells arrested at a promyelocytic stage by a leukemic transformation. However, experiments reported in this article indicate that the presence of PDT-treated tumor cells does not enhance the tumoricidal activity of macrophages directed against cells that are not treated with PDT.
None of the prior art reporting on the relationship of the immunologic system to PDT has explored the relationship between an enhanced neutrophil (white blood cell) count and a repetitive series of PDT treatments. Repetitive PDT treatments are most readily achieved with an implanted probe that can provide light therapy to adjacent abnormal tumor cells over an extended period of time. Even without modifying the body's immunologic response, such extended duration or repetitive PDT protocol has been found to provide substantial benefits relative to the more conventional approach of providing a single PDT treatment. As indicated above, prior research has shown that the efficacy of a single PDT treatment is enhanced by administering GM-CSF or G-CSF to a patient before the PDT treatment is provided. Various reasons have been advanced to explain these results. Although such explanations may prove correct, the prior research discussed above has not considered how administering GM-CSF or G-CSF after an initial PDT treatment might benefit subsequent PDT treatments and has not made any suggestions as to why such an approach might be of benefit.